Carboxamidine derivatives and their use in the treatment of vascular diseases

ABSTRACT

The subject invention relates to carboxamidine derivatives, to pharmaceutical compositions comprising the same, and the use thereof in the preparation of pharmaceutical compositions for the treatment of vascular diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.10/501,029, filed Jul. 25, 2005 now U.S. Pat. No. 7,384,936, which isthe U.S. national stage application of International patent applicationNo. PCT/HU03/00003, filed Jan. 10, 2003.

BACKGROUND OF THE INVENTION

The invention relates to pharmaceutically effective hydroxylaminederivatives, which are useful in the treatment of vascular diseases.

The invention relates to the use of compounds of general formulae (I),(II) and (III).

-   R¹ and R² independently represent a hydrogen atom or a straight or    branched C₁₋₆ alkyl group optionally substituted with a phenyl    group, or R¹ and R² together with the nitrogen atom attached thereto    form a 5-7 membered saturated heterocyclic ring optionally    containing further nitrogen and/or oxygen heteroatoms, which    heterocyclic ring is optionally substituted with one or more    hydroxy, oxo or benzyl groups,-   A represents a phenyl group optionally substituted with one or more    C₁₋₄ alkyl, C₁₋₄ haloalkyl or nitro groups or halogen atoms, or a    5-6 membered heteroaromatic ring containing one or more nitrogen,    oxygen or sulfur heteroatoms, optionally having N-oxide structure on    the nitrogen heteroatom,-   n is zero, 1 or 2,-   z is zero or 1,-   in compounds of general formulae (I), X represents a halogen atom or    —NR⁴R⁵ group, where R⁴ and R⁵ independently represent a hydrogen    atom or a straight or branched C₁₋₆ alkyl group,-   in compounds of general formulae (II), X refers to oxygen atom,-   R³ represents a hydrogen atom or a straight or branched C₁₋₆ alkyl    group, Y represents a hydrogen atom or hydroxy group, halogen atom    or C₁₋₂₂ acyloxy group, with the restriction that if R⁴ and R⁵ are    simultaneously hydrogen atoms, Y is other than hydroxy group,-   with the proviso that in compounds of general formulae (I) and (II)    where Y is other than halogen,

a) R¹ and R² together with the nitrogen atom attached thereto form a 5-7membered, saturated heterocyclic ring optionally containing furthernitrogen and/or oxygen heteroatom, which heterocyclic ring issubstituted with one or more hydroxy, oxo or benzyl groups and/or

b) A is a N-containing heteroaromatic ring, which has N-oxide structureon the nitrogen heteroatom, and/or

c) z is 1,

-   with the further proviso that if X is halo and Y is hydroxy or    acyloxy in compounds of general formulae (I),

R¹ and R² together with the nitrogen atom attached thereto form a 5-7membered, saturated heterocyclic ring optionally containing furthernitrogen and/or oxygen heteroatom, which heterocyclic ring issubstituted with one or more hydroxy, oxo or benzyl groups and

-   with the proviso for compounds of general formulae (III) that-   if R¹ and R² independently represent a hydrogen atom or a straight    or branched C₁₋₆ alkyl group optionally substituted with a phenyl    group, or together with the nitrogen atom attached thereto form a    5-7 membered saturated heterocyclic ring optionally containing    further nitrogen and/or oxygen heteroatoms, then A is a    heteroaromatic ring containing oxygen or sulfur heteroatom or an    N-containing heteroaromatic ring having N-oxide structure on the    nitrogen heteroatom and-   if A is a phenyl group optionally substituted with one or more C₁₋₄    alkyl, C₁₋₄ haloalkyl or nitro groups or halogen atoms, or a 5-6    membered N-containing heteroaromatic ring, then R¹ and R² together    with the nitrogen atom attached thereto form a 5-7 membered,    saturated heterocyclic ring optionally containing further nitrogen    and/or oxygen heteroatom, which heterocyclic ring is substituted    with one or more hydroxy, oxo or benzyl groups,-   and of the salts and optically active forms of the above compounds    for the production of pharmaceutical products used in the treatment    and/or prevention of vascular diseases or diseases related to    vascular disorders.

Compounds of similar structure are known from WO 97/16439. Thesecompounds increase molecular chaperon expression, or molecular chaperonactivity in cell exposed to a physiological stress. Due to thischaracteristic, they are useful for the treatment of diseases connectedwith the functioning of the chaperon system.

The protective and regenerating effect that compounds of similarstructures have for vascular endothelial cells is known from WO98/06400. These compounds are primarily useful for the prevention ofdamage caused by ischemia and for the treatment of cardiovascular andcerebrovascular diseases.

We have found that when the hydroxylamine derivatives described in thecited literature are chemically modified, preferably in such a way that,according to general formulae (I), (II) and (III) above,

1) a halogen atom is introduced into the propylene group of theaminopropyl group connected to the hydroxylamine part as substituentand/or

2) N-oxide is formed on the nitrogen atoms in the terminal groups of themolecule, namely on the nitrogen atom connected to the propylene groupof the above mentioned aminopropyl group and/or on the nitrogen atomlocated in the heteroaromatic ring of the molecule,

-   then the resulting products are hydroxylamine derivatives which    possess much more favorable pharmacological properties against    vascular illnesses than known compounds which have been found to be    useful for this purpose. Namely, the effect of these compounds is    more intensive than that of the known prior art compounds used for    similar purposes. Therefore they are especially useful as active    ingredients in the treatment or prevention of vascular diseases or    diseases associated with vascular disorders.

Based on this observation, this invention relates to the use ofcompounds of general formulae (I), (II) and (III)—where R¹R²R³, A, X, Y,n and z are as above—, and to the use of the salts and optically activeforms of the above compounds for the production of pharmaceuticalproducts for the treatment and/or prevention of vascular diseases ordiseases associated with vascular disorders.

A considerable part of compounds of general formulae (I), (II) and (III)are novel compounds.

Novel compounds are compounds of general formulae (I) wherein R¹ and R²independently represent a hydrogen atom or a straight or branched C₁₋₆alkyl group optionally substituted with a phenyl group, or R¹ and R²together with the nitrogen atom attached thereto form a 5-7 memberedsaturated heterocyclic ring optionally containing further nitrogenand/or oxygen heteroatoms, which heterocyclic ring is optionallysubstituted with one or more hydroxy, oxo or benzyl groups,

-   A represents a phenyl group optionally substituted with one or more    C₁₋₄ alkyl, C₁₋₄ haloalkyl or nitro groups or halogen atoms, or a    5-6 membered heteroaromatic ring containing one or more nitrogen,    oxygen or sulfur heteroatoms, optionally having N-oxide structure on    the nitrogen heteroatom,-   n is zero, 1 or 2,-   z is zero or 1,-   X represents a halogen atom or —NR⁴R⁵ group, where R⁴ and R⁵    independently represent a hydrogen atom or a straight or branched    C₁₋₆ alkyl group,-   Y represents a hydrogen atom or hydroxy group, halogen atom or C₁₋₂₂    acyloxy group, with the restriction that if R⁴ and R⁵ are    simultaneously hydrogen atoms, then Y is other than hydroxy group,-   with the proviso that

a) if Y is hydrogen and/or X is a —NR⁴R⁵ group, where R⁴ and R⁵ have theabove meanings,

R¹ and R² together with the nitrogen atom attached thereto form a 5-7membered, saturated heterocyclic ring optionally containing furthernitrogen and/or oxygen heteroatom, which heterocyclic ring issubstituted with one or more hydroxy, oxo or benzyl groups and/or

A is a N-containing heteroaromatic ring, which has N-oxide structure onthe nitrogen heteroatom, or

b) if X is halo and Y is hydroxy or acyloxy,

R¹ and R²together with the nitrogen atom attached thereto form a 5-7membered, saturated heterocyclic ring optionally containing furthernitrogen and/or oxygen heteroatom, which heterocyclic ring issubstituted with one or more hydroxy, oxo or benzyl groups,

-   and the stereoisomers of the above compounds and their salts.

Novel compounds are compounds of general formulae (II) wherein R¹ and R²independently represent a hydrogen atom or a straight or branched C₁₋₆alkyl group optionally substituted with a phenyl group, or R¹ and R²together with the nitrogen atom attached thereto form a 5-7 memberedsaturated heterocyclic ring optionally containing further nitrogenand/or oxygen heteroatoms, which heterocyclic ring is optionallysubstituted with one or more hydroxy, oxo or benzyl groups,

-   A represents a phenyl group optionally substituted with one or more    C₁₋₄ alkyl, C₁₋₄ haloalkyl or nitro groups or halogen atoms, or a    5-6 membered heteroaromatic ring containing one or more nitrogen,    oxygen or sulfur heteroatoms, optionally having N-oxide structure on    the nitrogen heteroatom,-   n is zero, 1 or 2,-   z is zero or 1,-   X represents an oxygen atom,-   R³ represents a hydrogen atom or a straight or branched C₁₋₆ alkyl    group,-   Y represents a hydrogen atom or hydroxy group, halogen atom or C₁₋₂₂    acyloxy group, with the proviso that if Y is other than halo,

R¹ and R² together with the nitrogen atom attached thereto form a 5-7membered, saturated heterocyclic ring optionally containing furthernitrogen and/or oxygen heteroatom, which heterocyclic ring issubstituted with one or more hydroxy, oxo or benzyl groups and/or

A is a N-containing heteroaromatic ring, which has N-oxide structure onthe nitrogen heteroatom,

-   and the stereoisomers of the above compounds and their salts.

Novel compounds are compounds of general formulae (III) wherein R¹ andR² independently represent a hydrogen atom or a straight or branchedC₁₋₆ alkyl group optionally substituted with a phenyl group, or R¹ andR² together with the nitrogen atom attached thereto form a 5-7 memberedsaturated heterocyclic ring optionally containing further nitrogenand/or oxygen heteroatoms, which heterocyclic ring is optionallysubstituted with one or more hydroxy, oxo or benzyl groups,

-   A represents a phenyl group optionally substituted with one or more    C₁₋₄ alkyl, C₁₋₄ haloalkyl or nitro groups or halogen atoms, or a    5-6 membered heteroaromatic ring containing one or more nitrogen,    oxygen or sulfur heteroatoms, optionally having N-oxide structure on    the nitrogen heteroatom,-   n is zero, 1 or 2,-   z is zero or 1,-   with the proviso that-   if R¹ and R² independently represent a hydrogen atom or a straight    or branched C₁₋₆ alkyl group optionally substituted with a phenyl    group,-   or together with the nitrogen atom attached thereto form a 5-7    membered saturated heterocyclic ring optionally containing further    nitrogen and/or oxygen heteroatoms, then 5 A is a heteroaromatic    ring containing oxygen or sulfur heteroatom or an N-containing    heteroaromatic ring having N-oxide structure on the nitrogen    heteroatom and if A is a phenyl group optionally substituted with    one or more C₁₋₄ alkyl, C₁₋₄ haloalkyl or nitro groups or halogen    atoms, or a 5-6 membered N-containing heteroaromatic ring, then R¹    and R² together with the nitrogen atom attached thereto form a 5-7    membered, saturated heterocyclic ring optionally containing further    nitrogen and/or oxygen heteroatom, which heterocyclic ring is    substituted with one or more hydroxy, oxo or benzyl groups,    and the stereoisomers of the above compounds and their salts.

The invention relates to the above compounds. The invention furtherrelates to 15 pharmaceutical products that contain as active ingredientcompounds of general formulae (I), (II) and (III), or theirstereoisomers, or their salts, where R¹, R², R³, A, X, Y, n and z are asdefined above.

The following compounds of the Invention are especially preferable:

-   1. N-[3-(1-piperidinyl)propoxy]-pyridin-1-oxide-3-carboxamidine-   2. N-[3-(1-piperidinyl)propoxy]-pyridin-1-oxide-3-carboximidoyl    chloride-   3.    N-[2-hydroxy-3-(1-piperidinyl)propoxy]-N′-n-butyl-pyridin-1-oxide-4-carboxamidine-   4. N-[3-(1-oxido-1-piperidinyl)propoxy]-3-nitro-benzimidoyl-chloride    dihydrate-   5. 2-chloro-N-[3-(4-oxido-4-morpholinyl)propoxy]-benzimidoyl    chloride-   6.    (R,S)-5,6-dihydro-5-[(1-piperidinyl)methyl]-3-(1-oxido-3-pyridyl)-4H-1,2,4-oxadiazine-   7.    5,6-dihydro-5-[(4-benzyl-1-piperidinyl)methyl]-3-(3-pyridyl)-4H-1,2,4-oxadiazine-   8. (R) or    (S)-5,6-dihydro-5-[(2-oxo-1-piperidinyl)methyl]-3-(3-pyridyl)-4H-1,2,4-oxadiazine-   9.    (+)-5,6-dihydro-5-[(1-piperidlnyl)methyl]-3-(1-oxido-3-pyridyl)4H-1,2,4-oxadiazine-   10. (R) or    (S)-5,6-dihydro-5-[(1-oxido-1-piperidinyl)methyl]-3-(1-oxido-3-pyridyl)-4H-1,2,4-oxadiazine-   11.    5.6-dihydro-5-[(4-hydroxy-1-piperidinyl)methyl]-3-(3-pyridyl)-4H-1,2,4-oxadiazine-   12. N-[2-chloro-3-(1-piperidinly)propoxyl]-benzimidoyl chloride    hydrochloride-   13.    N-[2-hydroxy-3-(1-piperidinyl)propoxy]-pyridin-1-oxide-3-carboxamide    -   The biological effects of the compounds of the invention were        tested by the following experiments:    -   Wounding migration assay in endothelial cell culture

The effect of the compounds of the invention on the wounded monolayersof human umbilical vein endothelial cells (HUVEC) were studied in a cellculture system (in vitro). After reaching confluence, the HUVEC cellswere wounded according to the method of Yamamura et al (J. Surgical Res.63, 349-354, 1996). The number of migrated cells were registered usingcomputerized image analysis 24 hours after wounding in the absence andpresence of the active agents under testing in a concentration of 10⁻⁶M. The active ingredient described in publication no. WO 98/06400,namely5,6-dihydro-5-(1-piperidinyl)-methyl-3-(3-pyridyl)-4H-1,2,4-oxadiazinewas used as reference compound. The obtained results are given in Table1.

TABLE 1 cell/mm² No. of the compound 24 hours Reference 30 4 45 8 48 952 11 51 12 60 13 54In the following, we give the results of the test of blood vesselrelaxing effect, performed in vitro on rat vessels, and also themorpholocial results of the thoracic aorta.

Three-month-old, genetically hypertonic (SH) Wistar Okamoto rats weretreated for one month with various test compounds. Thereafter thefunctional and morphological tests were performed.

The Vaso-relaxing Effect of the Compounds of the Invention on theThoracic Aorta of SH Rats (in Vitro Testing)

The test was performed by the method known from the literature [Japan J.Pharmacol., 59, 339-347 (1992)]. The SH rats were anesthetized withNembutal (40 mg/kg, i. p.), then the thoracic aorta was removed andplaced in oxygenized (95% O₂+5% CO₂) Krebs-Henseleit solution. Thecomposition of the solution (mM): NaCl 118, KCl 4,7, CaCl₂ 2,52, MgSO₄1,64, NaHCO₃ 24,88, KH₂PO₄ 1,18, glucose 5,5. The 3-mm-long aorta ringswere suspended in a 20 ml organ bath of 37° C. The resting tension was 1g, which was maintained throughout the equilibration. During the 1 hourequilibration, the medium was changed in every 20 minutes. The vesselswere contracted with 10⁻⁶ M methoxamine (approx. 80% of maximalcontraction). After reaching the maximal contraction, we tested thevasodilation resulting as the effect of the acetylcholine (Ach)(10⁻⁶-10⁻⁴ M), which informed us about the condition of the endotheliumof the vessel wall. The contraction force was measured by an isometricstrain gauge (SG-01D, Experimentia Ltd), and was registered on an OH-850polygraph (Radelkis). At this time again,5,6-dihydro-5-(1-piperidinyi)-methyl-3-(3-pyridyl)-4H-1,2,4-oxadiazineas described in WO 98/06400 was used as a reference compound. Theresults of these tests are summarized in Table 2.

TABLE 2 The vessel relaxing effect of the compounds of the invention onthe thoracic aorta of SH rats (in vitro testing) Materials Ach doses (M)Doses 10-6 10-5 10-4 SH control 55.1 57.2 72.0 n = 10 Reference 77.480.2 81.7 n = 12:20 mg/kg Compound no. 4. 82.5 84.9 88.1 n = 11; 5 mg/kgCompound no. 8. 80.3 88.0 89.2 n = 11; 20 mg/kg Compound no. 9. 87.087.9 93.2 n = 10; 5 mg/kg Compound no. 11. 79.7 85.1 86.0 n = 12; 10mg/kg Compound no. 12. 82.3 83.5 80.4 n = 12; 20 mg/kg Compound no. 13.88.4 90.3 95.2 n = 10

As the table shows, we registered a 30% relaxation decrease in the caseof untreated hypertonic animals, which is the result ofhypertonic-induced endothelial damage. The test compounds improved therelaxation properties of the vessels significantly, which is the resultof the improved functioning of the endothelium, due to the relativeincrease of the endothelium-related relaxation factors.

Morphological Testing of the Thoracic Aortas with Electron Microscopy

The test was performed according to the procedure known from theliterature (Br. J. of Pharmacol., 1995; 115, 415-420). 1 mm² pieces ofthe aorta wall was cut out of the thoracic aorta of the rats, and werethen fixed with 2.5% glutaraldehyde at room temperature for 2 hours.This was followed by a post-fixation with 1% osmium tetroxide for 1hour. Afterwards, the tissue pieces were dehydrated with ethanol, andembedded in Durcupan ACM. The samples were evaluated qualitatively basedon the images recorded on a Hitachi 7100 electron microscope. Theresults of the test are given in Table 3.

TABLE 3 Electron microscopic examination of the compounds of theinvention on the thoracic aorta of SH rats (morphological testing)Materials Doses Degree of regeneration SH control, physiological salinesolution 1 Compound no. 4., 20 mg/kg p.o. 5 Compound no. 8., 5 mg/kgp.o. 5 Compound no. 9., 5 mg/kg p.o. 5 Compound no. 11., 10 mg/kg p.o. 4Compound no. 12., 20 mg/kg p.o. 3 Compound no. 13., 20 mg/kg p.o. 4

The results of the morphological test are expressed on a scale of 1 to5, depending upon the degree to which the treatment with various testcompounds restored the hypertonia-induced endothelium damage, that is,upon the degree of regeneration activity observed. On the scale, 1 wasused to refer to cases where no regeneration was observable, 2 refers toweak, 3 to average, 4 to good, and 5 to strong regeneration.

When comparing it to the untreated control, significant protective andregenerative effect was observed after treatment with the compounds ofthe invention. Due to the treatment, a thin, freshly formed layercovered the wounded sub-endothelium, which contained cells with activenuclei and rich cytoplasm. Regeneration was shown to be very effectivein the case of the majority of the tested molecules.

Compounds of general formulae (I) where Y is a halogen atom are preparedby halogenating the suitable compound containing a hydroxyl group as Ysubstituent. The other compounds of the invention are prepared by theknown method, according to the procedures given in WO 97/16439 and WO98/06400. Methods for the preparation of certain compounds aredemonstrated in the examples.

The compositions of the invention can be made in solid or liquid formsgenerally used in human and veterinary therapy. For oral administrationtablets, coated tablets, dragé´es, granules, capsules, solutions orsyrups, for rectal administration suppositories, and for parenteraladministration lyophylised or not lyophylised injections or infusionsolutions can be prepared by known preparation methods. The oralcompositions may contain fillers such as microcrystalline cellulose,starch, lactose, lubricants, such as stearic acid and magnesiumstearate, coating materials such as sugar, film materials such ashydroxymethyl cellulose, flavors or sweeteners such as methyl paraben orsaccharine, and colorants. Auxiliaries in the suppositories may be forexample cocoa butter and polyethylene glycol. The compositions forparenteral use may contain saline or optional dispersing and wettingagents such as propylene glycol along with the active ingredient.

The dose of the compounds of the invention depends on the illness of thepatient and the disease and varies from 0.1 to 200 mg/kg/day, preferablyfrom 0.1 to 50 mg/kg/day. For human therapy, the preferable oral dose is10-200 mg, in case of rectal administration 1-15 mg, and in case ofparenteral treatment 2-20 mg daily for adults. These doses are appliedin unit dosage forms optionally distributed to 2-3 administrations,particularly in case of oral treatment.

The invention is demonstrated by the examples below.

EXAMPLE 1 N-[3-(1-piperidinyl)propoxy]-pyridin-1-oxide-3-carboxamidine

1.86 g (0.033 mol) of KOH is dissolved in a mixture of 10 ml ethanol and75 ml methanol. To the solution 4.59 g (0.03 mol) ofnicotinamidoxime-1-oxide is added. After stirring for 15 min a solutionof 4.85 g (0.03 mol) of 1-chloro-3-(1-plperidinyl)-propane in 6 mlethanol is added. The mixture is boiled for 12 hours, then theprecipitate is filtered off, and the solution is evaporated. To theresidue 30 ml of 2 N potassium carbonate solution is added, thenextracted 3 times with 50 ml of chloroform. The organic phase is washedwith 15 ml of 2 N potassium carbonate solution, dried over anhydrousmagnesium sulfate, filtered and evaporated. The crude product istriturated with 40 ml tert.butyl-methyl-ether. This procedure isrepeated, and the product obtained in the two steps is recrystallized ina 1:2 mixture of methanol and diethylether.

Yield: 1.72 g (21%). ¹H-NMR (methanol d₄): 8.62; 8.36; 7.82; 7.58; 4.22;2.3-2.6; 1.92; 1.3-1.6. ¹³C-NMR (methanol d₄): 149.4; 140.9; 138.0;134.5; 127.9; 73.3; 57.4; 55.6; 27.4; 26.7; 25.4.

EXAMPLE 2 N-[3-(1-piperidinyl)propoxy]-pyridin-1-oxlde-3-carboximidoylchloride

1.668 g (6.0 mmol) ofN-[3-(1-piperdinyl)-propoxy]-pyridin-1-oxide-3-carboxamidlne isdissolved in a 1:1 mixture of cc. HCl and water, then at 0° C. addeddropwise to a solution of 0.57 g (8.2 mmol) of NaNO₂ in 4 ml of water.The mixture is stirred for 2 hours at 0° C., then basified with 15 ml of20% NaOH solution. It is then extracted three times with 15 ml ofchloroform, the extract is dried over anhydrous sodium sulfate, filteredand evaporated. The residue is triturated with 15 ml of ether, filteredand dried. The precipitate is recrystallized from 6 ml of acetone.

Yield: 1.1 g (63%). ¹H-NMR (DMSO d₆): 8.56; 8.20; 7.98; 7.48; 2.4-2.6;1.92; 1.45; 1.3. ¹³C-NMR (DMSO d₆): 139.6; 136.7; 132.9; 132.3; 129.5and 126.5; 73.6; 53.9; 52,9; 24.1; 23.5; 22.0.

EXAMPLE 3N-[2-hydroxy-3-(1-piperidinyl)propoxy]-N′-n-butyl-pyridin-1-oxide-4-carboxamidlne

1.18 g ofN-[2-hydroxy-3-(1-piperidinyl)propoxy]-pyridin-1-oxide-4-carboximidoylchloride is dissolved in a mixture of 18 ml of n-butylamine and 10 ml of2-methoxyethyl-ether. The reaction mixture is heated under reflux for 24hours. The n-butylamine is evaporated from the mixture, and to theresidue 100 ml of 2 M potassium carbonate solution is added, then it isextracted 3 times with 10 ml of chloroform. The extract is dried overanhydrous sodium sulfate, filtered and evaporated. The obtained materialis recrystallized form ethylacetate.

Yield: 0.85 g (64%). ¹H-NMR (CDCl₃): 8.18; 7.36; 5.22; 4.06; 4.04; 2.97;2.62 and 2.42; 1.2-1.7; 0.86. ¹³C-NMR (CDCl₃): 153.1; 139.2; 129.2;125.5; 76.4; 65.5; 60.8; 54.6; 43.9; 33.3; 25.6; 23.9; 19.6; 13.6.

EXAMPLE 4N-[3-(1-oxido-1-piperidinyl)propoxy]-3-nitro-benzimidoyl-chloridedihydrate

To a solution of 1.0 g (3.0 mmol) ofN-[3-(1-piperidinyl)propoxy]-3-nitro-benzimidoyl-chloride in 5 ml ofchloroform a solution of 0.725 g (4.2 mmol) of m-chloroperbenzoic acidin 6 ml of chloroform is added. The reaction mixture is stirred for 6hours at 25 ° C., then evaporated. To the residue 12 ml of 2 M potassiumcarbonate solution is added, and extracted 5 times with 20 ml ofchloroform. The combined extracts are dried over magnesium sulfate,filtered and evaporated. The product is dissolved in ethanol; thesolution is treated with charcoal then evaporated. The obtained materialis triturated with ethylacetate, filtered and dried.

Yield: 0.74 g (63%). ¹H-NMR (CDCl₃): 8.62; 8.28; 8.18; 7.58; 4.52;3.1-3.6; 2,2-2.6; 1.3-1.8. ¹³C-NMR (CDCl₃): 148.2; 135.9; 134.0; 132.7;129.6; 125.0; 122.0; 73.7; 67.0; 65.4; 22.4; 22.1; 20.9.

EXAMPLE 5 2-chloro-N-(3-(4-oxido-4- morpholinyl)propoxy-bcnzimidoylchloride

Proceed according to Example 4, with the difference that as startingmaterial 2-chloro-N-[3-(4-morpholinyl) -propoxy]-benzimidoyl chloride isused. Yield: 82%.

EXAMPLE 6(R,S)-5,6-dihydro-5-[(1-piperidinyl)methyl]-3-(1-oxido-3-pyridyl)-4H-1,2,4-oxadiazine

a) 18.5 g (0.05 mol) ofN-[2-hydroxy-3-(1-piperidinyl)propoxy]-pyridin-1-oxide-3-carboxamidine-hydrochlorideis dissolved in 50 ml of thionylchloride, and the reaction mixture isheated under reflux for 1 hour. Next the reaction mixture is evaporated,the residue is dissolved in methanol, and the solution is treated withcharcoal, filtered and evaporated. The residue is crystallized from aminimum quantity of ethanol. The yield of the obtainedN-[2-chloro-3-(1-piperidinyl)propoxy]-pyridin-1-oxide-3-carboxamidinehydrochloride intermediate is 68%.

b) To a solution of 16.5 g (143.5 mmol) of potassium-tert.butylate in150 ml of tert.butanol 11.8 g (34.1 mmol)N-[2-chloro-3-(1-piperidinyl)propoxy]-pyridin-1-oxide-3-carboxamidinehydrochloride intermediate is added. The reaction mixture is boiled for5 hours, then evaporated. To the evaporation residue 100 ml of 5% NaOHsolution is added, and the mixture is extracted 3 times with 300 ml ofethylacetate. The combined extracts are dried over sodium-sulfate,filtered and evaporated. The evaporation residue is triturated withether, filtered, washed with ether and dried. Yield: 34%.

Mp.: 154-158° C.

EXAMPLE 75,6-dihydro-5-[(4-benzyl-1-piperidinyl)methyl]-3-(3-pyridyl)-4H-1,2,4-oxadiazine

Proceed according to Example 6, starting form the correspondingchlorinated amidine-compound.

Yield: 20%, Mp.: 178-180° C.

EXAMPLE 8 (R) or(S)-5,6-dihydro-5-[(2-oxo-1-piperidinyl)methyl]-3-(3-pyridyl)-4H-1,2,4-oxadiazine

2.5 g (9.6 mmol) of(−)-5,6-dihydro-5-(1-piperidinyl)-methyl-3-(3-pyridyl)-4H-1,2,4-oxadiazineis dissolved in 150 ml of 1% acetic acid, and to the solution 17.86 g(47.99 mmol) of ethylenediamine-tetraacetic acid disodium saltdihydrate, and 15.3 g (48 mmol) mercury(II)-acetate is added, and thereaction mixture is boiled for 2 hours while stirring. Then the reactionmixture is filtered, the filtrate is evaporated, to the residue 500 mlof methanol, and then in small portions 17.5 g (0.46 mol)sodium-[tetrahydrido-borate(III)] is added while stirring. Afteraddition of the borohydride its excess is decomposed with 1:1 aqueoushydrochloric acid (pH=3), then the pH of the reaction mixture is set to10 with 10% NaOH solution. The methanol is evaporated from the reactionmixture, and then the aqueous phase is extracted 3 times with 150 ml ofchloroform. The combined chloroform phases are washed first with 100 mlof water, then with 50 ml of brine, the organic phase is dried overmagnesium-sulfate, filtered and evaporated. The obtained oil (2 g) ispurified by column chromatography (Kieselgel 60, eluent: 1:1 mixture ofchloroform and methanol), and crystallized with a mixture ofethylacetate and ether (by the addition of very little amount ofethanol). 0.94 g (35.7%) pure material is obtained.

¹H-NMR: (CDCl₃): 8.9; 8.6; 7.92; 7.26; 6.68; 3.98; 3.96; 3.72-3.6;3.42-3.22; 2.30:1.76.

¹³C-NMR (CDCl₃): 172.2; 150.8; 150.4; 146.9; 133.2; 128.6; 123.3; 65.1;50.7; 50.5; 50.0; 32.1; 20.9.

EXAMPLE 9(+)-5,6-dihydro-5-[(1-piperidinyl)methyl]-3-(1-oxido-3-pyridyl)-4H-1,2,4-oxadiazine

6.25 g (24 mmol) of(−)-5,6-dihydro-5-(1-piperidinyl)-methyl-3-(3-pyridyl)-4H-1,2,4-oxadiazineis dissolved in a mixture of 40 ml of water, 6.85 ml (120 mmol) ofglacial acetic acid and 1.43 ml (24 mmol) of cc. H₂SO₄. The solution isheated to 60° C., and at this temperature 12 ml (75 mmol) of 21.5%hydrogen peroxide is added dropwise, and the reaction mixture is kept onstirring at this temperature. After 10 hours to the reaction mixturefurther 6 ml of 21.5% hydrogen peroxide is added dropwise. After another20 hours the reaction mixture is cooled to 0° C., and it is introduceddropwise into 60 ml of 0° C. 20% NaOH, then extracted 5 times with 50 mlof dichloromethane. The combined organic phases are washed with water,dried over magnesium-sulfate and evaporated. The evaporation residue ispurified by column chromatography. The suitable fractions are trituratedwith 20 ml of acetone and kept in refrigerator overnight. Next day theproduct is filtered, washed with cold acetone and dried, thenrecrystallized from ethanol-ethylacetate.

Yield: 13.7%. Mp.: 165-168° C.

EXAMPLE 10 (R) or(S)-5,6-dihydro-5-[(1-oxido-1-piperidinyl)methyl]-3-(1-oxrdo-3-pyridyl)-4H-1,2,4-oxadiazine

Proceed according to Example 9. with the difference that the suitablecolumn chromatographic fraction is isolated.

Yield: 3.4%. ¹H-NMR (D₂O): 8.38; 8.26; 7.76; 7.53; 4.6; 4.4; 3.9;3.55-3.1; 1.95-1.25. ¹³C-NMR (D₂O): 149.7; 139.9; 136.7; 131.6; 129.1;126.9; 69.2; 65.6; 65.5; 44.3; 20.46; 20.30 and 20.17.

EXAMPLE 115,6-dlhydro-5-[(4-hydroxy-1-piperidinyl)methyl]-3-(3-pyridyl)-4H-1,2,4-oxadiazine

20.55 g (150 mmol) of 3-pyridin-amidoxime and 20.1 g (360 mmol) ofpotassium hydroxide are dissolved in 95 ml of water and 28.5 ml of DMSO,then cooled to 0° C. At this temperature 20.85 g (17.7 ml, 225 mmol) ofepichlorohydrine is added dropwise and the mixture is stirred for 3hours. It is then extracted with 6×50 ml of ether, the combined organicphases are washed with 50 ml brine, dried over Na₂SO₄, treated withcharcoal, filtered and evaporated. m=6.08 g (21%)

The obtained evaporation residue is taken up in 90 ml of ether, theclear solution is decanted from the tar (1.18 g)—the ethereal solutioncontains 24.8 mmol epoxy compound—and to this solution 5.1 g (24.8 mmol)of 4-benzoyloxy-piperidine dissolved in 20 ml of iso-propanol is added.It is stirred at room temperature for 6 days, then the small amount ofprecipitate is filtered off, and the mother liquor is evaporated. Theobtained 11.7 g of evaporation residue is taken up in 100 ml of water,extracted with 100 ml of ether, then 2×50 ml of ethylacetate, theorganic phases are dried over Na₂SO₄ and evaporated. m=8.77 g (88%)

Formation of mono hydrochloride: 8.77 g of evaporation residue isdissolved in 44 ml iso-propanol (with slight heating), then 3.72 ml of6M HCl/iPA is added. Upon heating the solution to boiling point, theseparated gum dissolves. When it is then cooled back to roomtemperature, the monohydrochloride nicely precipitates. It iscrystallized in a 10 refrigerator for a few hours, then filtered off,and washed with cold iPA. m=7.19 g (75.4%) Mp.:115-120° C.Recrystallization: 7.19 g crude product form 150 ml of hot iso-propanol.Crystallizes upon cooling.

m=5.87 mg (81.5%)

Mp.: 117-120° C.

5.87 g (13.5 mmol) of this monohydrochloride is suspended in 60 ml ofdichloroethane, 30 ml of thionylchloride is added and is boiled for 1hour. It is then cooled back to room temperature, 220 ml of methanol isadded dropwise, treated with charcoal, filtered and evaporated. Theobtained 7.5 g evaporation residue is triturated with 75 ml ofethylacetate, and crystallized by cooling. Filtered, washed with coldethylacetate, then the wet precipitate is stirred with 50 ml of acetone.The precipitate is filtered off, and washed with acetone,

m=5.76 g (87%)

5.76 g (11.75 mmol) of this “chloro-compound” is suspended in 120 ml oftert.butanol, 8.12 g (72.37 mmol) of potassium-tert.butylate is addedand boiled for 1 hour. The precipitate is filtered and washed with asmall amount of methanol, and the mother liquor is evaporated. Theobtained 8.56 g of evaporation residue is taken up in 40 ml of water,extracted with 2×30 ml of chloroform, dried and evaporated. The residue(m=1.89 g) is triturated with 20 ml of ethylacetate, crystallized bycooling, filtered off, and washed with EtOAc.

m=1.19 g

Recrystallization: 1.19 mg of crude product from 13 ml of hotiso-propanol. Crystallizes upon cooling.

m=605 mg

Mp.: 170-173-^C ¹H-NMR (the examined sample: PM-720-cs₅; solvent:CDCl₃+DMSO; reference: CDCl₃: MHz: 300) [ppm]: 8.8 8.5 7.9 7.3 (m,4H,aromatic protons); 6.1 (m, 1H,NH); 4.02 (m, 1H,OCH₂); 3.74 (m,1H,CH); 3.62 (m, 1H, CH—OH); 3.5 (m, 1H, OCH₂); 2.9-2.3 (m, 6H, 3×CH₂N);1.9-1.52 (m, 4H, 2×CH₂): ¹³C-NMR (the examined sample: PM-720-cs₅;solvent: CDCl₃+DMSO; reference: CDCl₃;MHz:75.4)[ppm]: 150.4 (C═N); 150.9146.9 133.5 128,6 123.3 (5C, Pyr-carbon atoms); 66.6 OCH₂); 66.4(CH—OH); 59.4 (CH₂N); 51.8 (CH₂N); 50.7 (CH₂N); 46.3 (CHN); 33.8 (2C,2×CH₂)

EXAMPLE 12 N-[2-chloro-3-(1-pioeridinly)provoxyl]-benzimidoyl chloridehydrochloride

2.0 g of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-benzimidoyl-chloridehydrochloride is dissolved in 10 ml of thionylchloride, then thesolution is boiled for 2 hours. The thionylchloride is distilled off;the evaporation residue is taken up in 50 ml of methanol, thenevaporated. The light yellow evaporation residue (m=2.48 g) is dissolvedin 12.5 ml of ethanol and crystallized with 50 ml of ether. Theseparated precipitate is filtered off, and washed with a mixture ofethanol/ether.

m=1.68 g Mp.: 154.5-158° C. Recrystallization: by dissolving 320 mg in 1ml warm MeOH, then precipitating with 3 ml of ether. The separatedprecipitate is filtered off and washed. m=210 mg Mp.:155.5-160°C.(corr.)

EXAMPLE 13N-[2-hydroxy-3-(1-piperidinyl)propoxy]-pyrldin-1-oxide-3-carboxamide

4.0 g ofN-[2-hydroxy-3-(1-piperidinyl)propoxy]-pyridin-1-oxide-3-carboximidoyl-chlorideis stirred in 120 ml of 0.2 n NaOH at 60° C. for 5 days. The solution isneutralized with aqueous hydrochloric acid, evaporated, the residue istriturated with ethanol, and the obtained solution is evaporated again.The residue is crystallized with isopropanol, filtered off, and theobtained 1.0 g crude product is recrystallized from boiling isopropanol.

Yield: 0.8 g Mp.: 143-147° C.

EXAMPLE 14

Tablets (+)-5,6-dihydro-5-[(1-piperidinyl)methyl-3- 20.0 mg(3-pyridyl)-4H-1,2,4-oxadiazine corn starch 100.0 mg lactose 95.0 mgtalc 4.5 mg magnesium stearate 0.5 mg

The active compound is finely ground, mixed with the excipients, themixture 25 is homogenized and granulated. The granulate is pressed intotablets.

EXAMPLE 15

Capsules 5,6-dihydro-5-[(1-piperidinyl)-methyl-3- 20.0 mg(3-pyridyl)-4H-1,2,4-oxadiazine microcrystalline cellulose 99.0 mgamorphous silica  1.0 mg

The active ingredient is mixed with the additives, the mixture ishomogenized and filled into gelatine capsules.

EXAMPLE 16

Dragées N-[3-(1-oxido-1-piperidinyl)propoxy]-3- 25.0 mgnitro-benzimidoyl-chloride dihydrate lactose 82.5 mg potato starch 33.0mg polyvinyl pyrrolidone  4.0 mg magnesium stearate  0.5 mg

The active ingredient and the polyvinyl pyrrolidone are dissolved inethanol. The lactose 10 and the potato starch are mixed, and the mixtureis evenly wetted with the granulating solution of the active ingredient.After sieving, the wet granulate it is dried at 50° C. and sieved.Magnesium stearate is added and the granulate is pressed into dragéecores, which are then coated with sugar and polished with bee wax.

EXAMPLE 17

Suppositories 5,6-dihydro-5-[(4-benzyl-1-piperidinyl)-methyl]-3- 4.0 mg(3-pyridyl)--4H-1,2.4-oxadiazine cocoa butter 3.5 g solid fat 50suppository mass 15.0 g

The cocoa butter and the suppository mass are heated to 40° C., theactive ingredient is dispersed in the melt, then the mass is cast intosuppository forms.

EXAMPLE 18

Solution 5,6-dihydro-5-[(4-hydroxy-1-piperidinyl)methyl]- 500 mg3-(3-pyridyl)-4H-1,2,4-oxadiazine hydrochloride sorbite 10 g saccharinsodium 0.05 g twice distilled water q.s. ad 100 mi

EXAMPLE 19

Injection N-[2-chloro-3-(1-piperidinyl)propoxy]- 2 mgbenzimidoyl-chloride hydrochloride physiological saline solution, q.s.ad 2.0 ml pyrogen-free, sterile

The solution is filled into 2 ml vials and the vials are sealed.

EXAMPLE 20

Infusion solution Infusion solution of 500 ml volume is prepared withthe following composition:N-[2-hydroxy-3-(1-piperidinyl)propoxy]-pyridin-1- 20 mgoxide-3-carboxamide methanesulfonate physiological saline solution, q.s.ad 500 ml pyrogen-free, sterile

1. A method for treating a vascular disease or a vascular disordercomprising administering to a patient in need thereof an effectiveamount of a compound of formula I or II as defined below: i) a compoundof formula I:

wherein R¹ and R² are independently hydrogen, a straight chained C₁₋₆alkyl group optionally substituted with a phenyl group, or a branchedC₁₋₆ alkyl group optionally substituted with a phenyl group, or R¹ andR² together with the nitrogen atom attached thereto form a 5-7 memberedsaturated heterocyclic ring optionally containing further nitrogenand/or oxygen heteroatoms, wherein the heterocyclic ring is optionallysubstituted with one or more hydroxy, oxo or benzyl groups; A is aphenyl group optionally substituted with one or more C₁₋₄ alkyl, C₁₋₄haloalkyl, nitro, or halogen, or is a 5-6 membered heteroaromatic ringcontaining at least one heteroatom selected from nitrogen, oxygen andsulfur, wherein the nitrogen heteroatom is optionally a N-oxidestructure; n is 0, 1, or 2; z is 0 or 1; X is halogen or —NR⁴R⁵, whereinR⁴ and R⁵ are independently hydrogen, a straight chained C₁₋₆ alkylgroup or a branched C₁₋₆ alkyl group, Y is a hydrogen, hydroxy group,halogen, or C₁₋₂₂ acyloxy group, wherein if R⁴ and R⁵ are both hydrogen,then Y is other than a hydroxy group, with the proviso that a) if Y ishydrogen and/or X is an —NR⁴R⁵ or if X is —NR⁴R⁵ group, then R¹ and R²together with the nitrogen atom attached thereto form a 5-7 membered,saturated heterocyclic ring optionally containing further nitrogenand/or oxygen heteroatoms, wherein the heterocyclic ring is substitutedwith one or more hydroxy, oxo, or benzyl groups, and/or A is a nitrogencontaining heteroaromatic ring, wherein said ring has an N-oxidestructure on the nitrogen heteroatom, or b) if X is halogen and Y ishydroxy or acyloxy, then n is 1 or 2 , and R¹ and R² together with thenitrogen atom attached thereto form a 5-7 membered, saturatedheterocyclic ring optionally containing further nitrogen and/or oxygenheteroatoms, wherein said heterocyclic ring is substituted with one ormore hydroxy, oxo or benzyl groups, or a stereoisomer or salt thereof;ii) a compound of formula II:

wherein R¹ and R² are independently hydrogen, a straight chained C₁₋₆alkyl group optionally substituted with a phenyl group, a branched C₁₋₆alkyl group optionally substituted with a phenyl group, or R¹ and R²together with the nitrogen atom attached thereto form a 5-7 memberedsaturated heterocyclic ring optionally containing further nitrogenand/or oxygen heteroatoms, wherein said heterocyclic ring is optionallysubstituted with one or more hydroxy, oxo or benzyl groups, A is aphenyl group optionally substituted with one or more C₁₋₄ alkyl, C₁₋₄haloalkyl, nitro, or halogen, or is a 5-6 membered heteroaromatic ringcontaining at least one heteroatom selected from nitrogen, oxygen, andsulfur, wherein the nitrogen heteroatom is optionally an N-oxidestructure; n is 0, 1, or 2; z is 0 or 1; X is oxygen; R³ is selectedfrom hydrogen, straight chained C₁₋₆ alkyl group, and branched chainedC₁₋₆ alkyl group; Y is selected from hydrogen, hydroxy, halogen, andC₁₋₂₂ acyloxy group, with the proviso that if Y is other than halogen,then n is 1 or 2, and R¹ and R² together with the nitrogen atom attachedthereto form a 5-7 membered, saturated heterocyclic ring optionallycontaining further nitrogen and/or oxygen heteroatoms, wherein saidheterocyclic ring is substituted with one or more hydroxy, oxo or benzylgroups and/or A is a nitrogen containing heteroaromatic ring, which hasN-oxide structure on the nitrogen heteroatom; or a stereoisomer or saltthereof.
 2. The method according to claim 1, wherein the compound isN-[3-(1-piperidinyl)propoxy]-pyridin-1-oxide-3-carboxamidine or a saltthereof.
 3. The method according to claim 1, wherein the compound isN-[3-(1-piperidinyl)propoxy]-pyridin-1-oxide-3-carboximidoyl chloride.4. The method according to claim 1, wherein the compound isN-[2-hydroxy-3-(1-piperidinyl)propoxy]-N′-n-butyl-pyridin-1-oxide-4-carboxamidine,or a stereoisomer or salt thereof.
 5. The method according to claim 1,wherein the compound isN-[3-(1-oxido-1-piperidinyl)propoxy]-3-nitro-benzimidoyl chloride, or ahydrate and/or salt thereof.
 6. The method according to claim 1, whereinthe compound is2-chloro-N-[3-(4-oxido-4-morpholinyl)propoxy]-benzimidoyl chloride or asalt thereof.
 7. The compound according to claim 1, wherein the compoundis N-[2-chloro-3-(1-piperidinyl)propoxy]-3-benzimidoyl chloridehydrochloride, or a stereoisomer or salt thereof.
 8. The compoundaccording to claim 1, wherein the compound isN-[2-hydroxy-3-(1-piperidinyl)propoxy]-pyridin-1-oxide-3-carboxamide, ora stereoisomer or salt thereof.
 9. A method for inhibiting or reversingdamage to one or more endothelial cells comprising administering to theone or more endothelial cells an effective amount of a compound offormula I or II as defined below: i) a compound of formula I:

wherein R¹ and R² are independently hydrogen, a straight chained C₁₋₆alkyl group optionally substituted with a phenyl group, or a branchedC₁₋₆ alkyl group optionally substituted with a phenyl group, or R¹ andR² together with the nitrogen atom attached thereto form a 5-7 memberedsaturated heterocyclic ring optionally containing further nitrogenand/or oxygen heteroatoms, wherein the heterocyclic ring is optionallysubstituted with one or more hydroxy, oxo or benzyl groups; A is aphenyl group optionally substituted with one or more C₁₋₄ alkyl, C₁₋₄haloalkyl, nitro, or halogen, or is a 5-6 membered heteroaromatic ringcontaining at least one heteroatom selected from nitrogen, oxygen andsulfur, wherein the nitrogen heteroatom is optionally an N-oxidestructure; n is 0, 1, or 2; z is 0 or 1; X is halogen or —NR⁴R⁵, whereinR⁴ and R⁵ are independently hydrogen, a straight chained C₁₋₆ alkylgroup or a branched C₁₋₆ alkyl group, Y is a hydrogen, hydroxy group,halogen, or C₁₋₂₂ acyloxy group, wherein if R⁴ and R⁵ are both hydrogen,then Y is other than a hydroxy group, with the proviso that a) if Y ishydrogen and/or X is an —NR⁴R⁵ or if X is —NR⁴R⁵ group, then R¹ and R²together with the nitrogen atom attached thereto form a 5-7 membered,saturated heterocyclic ring optionally containing further nitrogenand/or oxygen heteroatoms, wherein the heterocyclic ring is substitutedwith one or more hydroxy, oxo, or benzyl groups, and/or A is a nitrogencontaining heteroaromatic ring, wherein said ring has an N-oxidestructure on the nitrogen heteroatom, or b) if X is halogen and Y ishydroxy or acyloxy, then n is 1 or 2, and R¹ and R² together with thenitrogen atom attached thereto form a 5-7 membered, saturatedheterocyclic ring optionally containing further nitrogen and/or oxygenheteroatom, wherein said heterocyclic ring is substituted with one ormore hydroxy, oxo or benzyl groups, or a stereoisomer or salt thereof;ii) a compound of formula II

wherein R¹ and R² are independently hydrogen, a straight chained C₁₋₆alkyl group optionally substituted with a phenyl group, a branched C₁₋₆alkyl group optionally substituted with a phenyl group, or R¹ and R²together with the nitrogen atom attached thereto form a 5-7 memberedsaturated heterocyclic ring optionally containing further nitrogenand/or oxygen heteroatoms, wherein said heterocyclic ring is optionallysubstituted with one or more hydroxy, oxo or benzyl groups, A is aphenyl group optionally substituted with one or more C₁₋₄ alkyl, C₁₋₄haloalkyl, nitro, or halogen, or is a 5-6 membered heteroaromatic ringcontaining at least one heteroatom selected from nitrogen, oxygen andsulfur, wherein the nitrogen heteroatom is optionally an N-oxidestructure; n is 0, 1, or 2; z is 0 or 1; X is oxygen; R³ is selectedfrom hydrogen, straight chained C₁₋₆ alkyl group, and branched chainedC₁₋₆ alkyl group; Y is selected from hydrogen, hydroxy, halogen, andC₁₋₂₂ acyloxy group, with the proviso that if Y is other than halogen,then n is 1 or 2, and R¹ and R² together with the nitrogen atom attachedthereto form a 5-7 membered, saturated heterocyclic ring optionallycontaining further nitrogen and/or oxygen heteroatom, wherein saidheterocyclic ring is substituted with one or more hydroxy, oxo or benzylgroups and/or A is a nitrogen containing heteroaromatic ring, which hasN-oxide structure on the nitrogen heteroatom; or a stereoisomer or saltthereof.
 10. The method according to claim 9, wherein the compound isN-[3-(1 -piperidinyl)propoxy]-pyridin-1-oxide-3-carboxamidine or a saltthereof.
 11. The method according to claim 9, wherein the compound isN-[3-(1-piperidinyl)propoxy]-pyridin-1-oxide-3-carboximidoyl chloride.12. The method according to claim 9, wherein the compound isN-[2-hydroxy-3-(1-piperidinyl)propoxy]-N′-n-butyl-pyridin-1-oxide-4-carboxamidine,or a stereoisomer or salt thereof.
 13. The method according to claim 9,wherein the compound isN-[3-(1-oxido-1-piperidinyl)propoxy]-3-nitro-benzimidoyl chloride, or ahydrate and/or salt thereof.
 14. The method according to claim 9,wherein the compound is2-chloro-N-[3-(4-oxido-4-morpholinyl)propoxy]-benzimidoyl chloride or asalt thereof
 15. The method according to claim 9, wherein the compoundis N-[2-chloro-3-(1-piperidinyl)propoxy]-3-benzimidoyl chloridehydrochloride, or a stereoisomer or salt thereof.
 16. The methodaccording to claim 9, wherein the compound isN-[2-hydroxy-3-(1-piperidinyl)propoxy]-pyridin-1-oxide-3-carboxamide, ora stereoisomer or salt thereof.
 17. The method of claim 9, wherein thecompound is administered to one or more of the endothelial cells inculture.
 18. The method of claim 9, wherein the compound is administeredto one or more endothelial cells of a patient.
 19. The method accordingto claim 1, wherein the compound is a compound of formula I.
 20. Themethod according to claim 19, wherein R¹ and R² together with thenitrogen atom attached thereto form piperidinyl or morpholino ringoptionally substituted with one or more hydroxy, oxo, or benzyl groups,A is a phenyl group optionally substituted with one or more nitrogroups, or a pyridinyl group optionally substituted with one or moreC₁₋₄ alkyl groups, wherein the nitrogen of the pyridinyl group isoptionally a N-oxide structure, z=0 or 1, X is halogen or —NR⁴R⁵,wherein R⁴ and R⁵ are independently hydrogen, a straight chained C₁₋₆alkyl group or a branched C₁₋₆ alkyl group, Y is a hydrogen, hydroxygroup, or halogen; or a stereoisomer or salt thereof.
 21. The methodaccording to claim 9, wherein the compound is a compound of formula I.22. The method according to claim 21, wherein R¹ and R² together withthe nitrogen atom attached thereto form piperidinyl or morpholino ringoptionally substituted with one or more hydroxy, oxo, or benzyl groups,A is a phenyl group optionally substituted with one or more nitro group,or a pyridinyl group optionally substituted with one or more C₁₋₄ alkylgroup, wherein the nitrogen of the pyridinyl group is optionally aN-oxide structure, z=0 or 1, X is halogen or —NR⁴R⁵, wherein R⁴ and R⁵are independently hydrogen, a straight chained C₁₋₆ alkyl group or abranched C₁₋₆ alkyl group, Y is a hydrogen, hydroxy group, or halogen;or a stereoisomer or salt thereof.
 23. A method for increasingvaso-relaxation of a vessel associated with endothelial cells comprisingadministering to the cells an effective amount of a compound of formulaI or II as defined below: i) a compound of formula I:

wherein R¹ and R² are independently hydrogen, a straight chained C₁₋₆alkyl group optionally substituted with a phenyl group, or a branchedC₁₋₆ alkyl group optionally substituted with a phenyl group, or R¹ andR² together with the nitrogen atom attached thereto form a 5-7 memberedsaturated heterocyclic ring optionally containing further nitrogenand/or oxygen heteroatoms, wherein the heterocyclic ring is optionallysubstituted with one or more hydroxy, oxo or benzyl groups; A is aphenyl group optionally substituted with one or more C₁₋₄ alkyl, C₁₋₄haloalkyl, nitro or halogen, or is a 5-6 membered heteroaromatic ringcontaining at least one heteroatom selected from nitrogen, oxygen, andsulfur, wherein the nitrogen heteroatom is optionally an N-oxidestructure; n is 0, 1, or 2; z is 0 or 1; X is halogen or —NR⁴R⁵, whereinR⁴ and R⁵ are independently hydrogen, a straight chained C₁₋₆ alkylgroup or a branched C₁₋₆ alkyl group, Y is a hydrogen, hydroxy group,halogen, or C₁₋₂₂ acyloxy group, wherein if R⁴ and R⁵ are both hydrogen,then Y is other than a hydroxy group, with the proviso that a) if Y ishydrogen and/or X is an —NR⁴R⁵ or if X is —NR⁴R⁵ group, then R¹ and R²together with the nitrogen atom attached thereto form a 5-7 membered,saturated heterocyclic ring optionally containing further nitrogenand/or oxygen heteroatoms, wherein the heterocyclic ring is substitutedwith one or more hydroxy, oxo, or benzyl groups, and/or A is anitrogen-containing heteroaromatic ring, wherein said ring has anN-oxide structure on the nitrogen heteroatom, or b) if X is halogen andY is hydroxy or acyloxy, then n is 1 or 2, and R¹ and R² together withthe nitrogen atom attached thereto form a 5-7 membered, saturatedheterocyclic ring optionally containing further nitrogen and/or oxygenheteroatoms, wherein said heterocyclic ring is substituted with one ormore hydroxy, oxo or benzyl groups, or a stereoisomer or salt thereof;ii) a compound of formula II

wherein R¹ and R² are independently hydrogen, a straight chained C₁₋₆alkyl group optionally substituted with a phenyl group, a branched C₁₋₆alkyl group optionally substituted with a phenyl group, or R¹ and R²together with the nitrogen atom attached thereto form a 5-7 memberedsaturated heterocyclic ring optionally containing further nitrogenand/or oxygen heteroatoms, wherein said heterocyclic ring is optionallysubstituted with one or more hydroxy, oxo or benzyl groups, A is aphenyl group optionally substituted with one or more C₁₋₄ alkyl, C₁₋₄haloalkyl, nitro, or halogen, or is a 5-6 membered heteroaromatic ringcontaining at least one heteroatom selected from nitrogen, oxygen, andsulfur, wherein the nitrogen heteroatom is optionally an N-oxidestructure; n is 0, 1, or 2; z is 0 or 1; X is oxygen; R³ is selectedfrom hydrogen, straight chained C₁₋₆ alkyl group, and branched chainedC₁₋₆ alkyl group; Y is selected from hydrogen, hydroxy, halogen, andC₁₋₂₂ acyloxy group, with the proviso that if Y is other than halogen,then n is 1 or 2, and R¹ and R² together with the nitrogen atom attachedthereto form a 5-7 membered, saturated heterocyclic ring optionallycontaining further nitrogen and/or oxygen heteroatoms, wherein saidheterocyclic ring is substituted with one or more hydroxy, oxo or benzylgroups and/or A is a nitrogen-containing heteroaromatic ring, which hasa N-oxide structure on the nitrogen heteroatom; or a stereoisomer orsalt thereof.
 24. The method of claim 23, wherein the compound isadministered to one or more of the endothelial cells in culture.
 25. Themethod of claim 23, wherein the compound is administered to one or moreendothelial cells of a patient.
 26. The method according to claim 23,wherein the compound is a compound of formula I.
 27. The methodaccording to claim 26, wherein R¹ and R² together with the nitrogen atomattached thereto form piperidinyl or morpholino ring optionallysubstituted with one or more hydroxy, oxo, or benzyl groups, A is aphenyl group optionally substituted with one or more nitro groups, or apyridinyl group optionally substituted with one or more C₁₋₄ alkylgroups, wherein the nitrogen of the pyridinyl group is optionally aN-oxide structure, z=0 or 1, X is halogen or —NR⁴R⁵, wherein R⁴ and R⁵are independently hydrogen, a straight chained C₁₋₆ alkyl group or abranched C₁₋₆ alkyl group, Y is a hydrogen, hydroxy group, or halogen;or a stereoisomer or salt thereof.